Update on Drug Interactions of HIV/HCV Treatment Regimens

Jennifer J. Kiser, PharmD Associate Professor University of Colorado

Disclosures

• Dr. Kiser receives research funding (paid to her institution) from ViiV Healthcare.

• Janssen Scientific Affairs - ended 12/15

• Dr. Kiser received research funding (paid to her

institution) from Janssen Scientific Affairs (ended 12/15).

Objectives

• Compare the pharmacology of HCV treatments in someone with HIV

• Describe key drug-drug interactions between HCV and antiretroviral therapies

• Explore key drug-drug interactions with other medications commonly used among HIV-coinfected persons

CYP450 and Drug Metabolism

CYP1A2 CYP2E1

CYP3A4

CYP2C

CYP2D6

Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed.

Key points

• Majority of drugs metabolizedby (or substrates for) CYP3A4

• Enzymes can be induced orinhibited

CYP450 Inhibition

Inhibiting drug added (RTV)

Time

Drug Concentration

Key Points •CYP450 inhibition leads to increased levels of drugs metabolized by same enzyme. Drug toxicity possible. •Peak effect occurs rapidly, as soon as adequate concentrations of inhibitor are reached

CYP450 Induction

Time

Drug Concentration

Inducing drug added (RIF) Key Points •CYP450 induction leads to decreased levels of drugs metabolized by same enzyme. •Peak effect occurs slowly based upon half-life of drug and time to synthesize new CYP450 enzyme

Bile

NTCP

OATP1B1 OATP1B3 OATP2B1

OAT2

Systemic Circulation Systemic Circulation

Transporters in the Liver

OCT1 P-gp

MRP2 MRP3

MRP4

BCRP ABCG5/G8

BSEP

MDR3

Adapted from Oswald S. et al. Xenobiotica 2007;37(10-11):1171-95.

Sinusoidal Membrane Canalicular Membrane

Like enzymes, transporters can also be inhibited or induced.

Sofosbuvir

• NS5B Polymerase Inhibitor • Uridine nucleotide analog • 80% renally eliminated • In plasma, SOF accounts for only ~4% of the drug related

material, majority (>90%) is GS-331007 (“007”)

Enzymes Transporters

Victim Substrate P-gp and BCRP

Perpetrator

SOF SOF

007-TP 007

Plasma Cell

Sofosbuvir and Amiodarone

• 9 cases (3 on SOF/LDV, 5 on SOF/DCV, 1 on SIM/SOF) • bradycardia, fatal cardiac arrest, some cases requiring

pacemaker insertion • For patients taking amiodarone with no alternative,

counseling and cardiac monitoring in an in-patient setting for the first 48 hours of SOF/LDV co-administration is recommended with daily heart rate monitoring x 2 weeks.

• Mechanism unclear Gilead Dear Healthcare provider letter issued 3/20/15

Ledipasvir

• Minimal metabolism, 70% eliminated unchanged, 1% renally eliminated

• Absorption is pH-dependent

Enzymes Transporters

Victim “Unknown pathway”, CYP3A4? Substrate P-gp

Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3

LDV dosing with gastric acid modifiers

• Separate antacids by 4 hours. • PPI doses comparable to

omeprazole 20mg can be administered simultaneously with SOF/LDV under fasted conditions.

• H2 blocker doses should not exceed the equivalent of famotidine 40mg BID.

• Avoid if possible.

Equivalent PPI Doses

Esomeprazole 40mg

Pantoprazole 40mg

Lansoprazole 30mg

Rabeprazole 20mg

Omeprazole 20mg

PPI use may compromise SVR with SOF/LDV

• HCV-Target is a multicenter, prospective, observational cohort

• Odds of SVR in individuals not receiving a PPI were 2.47-times those of individuals taking a PPI

HCV Target. Terrault N, et al. AASLD 2015

RTV-Boosted PIs

Without With

LDV/SOF4-9 LDV/SOF10

With SOF/LDV, TFV exposures are high in those on PIs

EFV RPV ATR CPA

NNRTIs

Without With LDV/SOF1,2 LDV/SOF3

• TFV exposures are higher when TDF is coadministered with LDV/SOF compared to without LDV/SOF, but • Compared to the range of TFV exposures with available safety data

• For EFV or RPV: TFV exposures fall within the range1

• For RTV-boosted PIs: TFV exposures partially exceed the range2

Range of TFV exposures with available safety

data

1, Data on File, Gilead Sciences. 2. Hoetelmans RMW, et al. 6th IWCPHT 2005. Quebec City, Canada. Poster #2.11 3. German P, et al. ICPHHT 2014. #O6 4. Luber AD, et al. HIV Medicine. 2010;11:193-9 (FPV+RTV) 5. Chittick GE, et al. AAC. 2006; 50(4):1304-10 (SQV+RTV)

6. Zhu. 9th IWCPHT. 2008. #023 (ATV+RTV & LPV/r ) * HIV-infected subjects in CASTLE study 7. Kearney B, et al. JAIDS. 2006;43(3):278-83 (LPV/r) 10. German P, et al. CROI 2015 8. Agarwala S, et al. 6th IWCPHT 2005. #16. (ATV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 2007;64(5):655-61 (DRV+RTV)

N = 30 15 17 14 FPV SQV LPV/r ATV DRV ATV DRV

15 35 19* 24 17* 14 12 24 23

Guidelines Recommendation on SOF/LDV with TDF

• SOF/LDV and TDF should be avoided in those with CrCl below 60 mL/min

• The combination of SOF/LDV with TDF and boosted regimens should be avoided (pending further data) unless antiretroviral regimen cannot be changed and the urgency of treatment is high

www.HCVguidelines.org

If you can’t avoid TDF + boosted regimen, monitor

• Baseline parameters should include estimated renal function, electrolytes (including phosphorus), and urinary protein and glucose levels

• Monitor every 2-4 weeks on therapy • Estimated renal function

• CKD in HIV guidelines suggest using CKD-EPI equation • Urinary protein and glucose

Lucas GM, et al. CID 2014;59(9):e96-138, www.HCVguidelines.org

Renal Safety of “Boosted TDF” in HIV/HCV-patients on SOF/LDV

Vivancos-Gallego MJ, et al. CROI, 2/22-2/25, 2016, Boston, MA, #452

• Average eGFR appeared to decline slightly with the initiation of SOF/LDV, but

• No difference in eGFR in those on TDF plus boosted PI vs. without boosted PI

• At end of treatment, no difference between groups in those with eGFR < 70 mL/min

Tenofovir Alafenamide (TAF) lower TFV plasma levels

Lymphoid Cells Plasma Gut TFV

TFV-MP

TFV-DP

TDF TDF TDF

TFV TFV

TAF TAF TAF TFV

Tenofovir alafenamide (TAF)

Tenofovir disoproxil fumarate (TDF)

Tenofovir (TFV)

• Intact TAF transits directly into target cells where it is intracellularly activated to tenofovir diphosphate (TFV-DP)1-3 • TAF has 90% lower circulating plasma TFV levels compared to TDF 300mg4-6 • Basolateral transporters (OAT1, OAT3) effectively transfer TFV, but not intact TAF, into renal proximal tubular cells7

• Lower systemic level of TFV, improved renal safety profile8-10

1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 7. Bam R, et al. Antiviral ther. 2014. 2014 Apr 4 [Epub] 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. 8. Ruane P, et al. JAIDS 2013;63:449-455. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 6. Sax P, et al. CROI 2015. Seattle, WA. #143LB 9. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8.

10. Mills A, et al. ICAAC 2014 . Washington D.C. Abstract# H-647c.

TAF – Possible TDF Alternative in Patients on Cobicistat and Ritonavir

Garrison KL, et al. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Alexandria, VA, May 26-28, 2015, abstract 71.

• TFV was increased by SOF/LDV in those on F/TAF/ELV/cobi by 27%, but • TFV AUC with TAF only ~20% of AUC typically seen with TDF (~400 vs. 2000 ng*hr/mL)

Velpatasvir

• pH dependent absorption • More reliant on hepatic metabolism than LDV • <1% of the dose is excreted in urine

Enzymes Transporters

Victim CYP3A4, CYP2C8, CYP2B6 Substrate P-gp, BCRP

Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3

Mogalian E, et al. Clin Pharmacokin Epub Oct 30, 2015

VEL absorption is pH-dependent

• Unlike the current guidance with ledipasvir, recommended to take the 20mg OME equivalent in the fed state

• VEL exposures in the healthy volunteers receiving 20mg OME in the fed state similar to VEL exposures in Phase 3 trials

Mogalian E, et al. ASCPT, 3/8-3/12, 2016, San Diego, CA, #PI-050

Velpatasvir Interactions with ARV

• Cannot be used with EFV

Mogalian E, et al. AASLD 11/13-11/17, 2015, Boston, MA #

• Tenofovir Levels Increased

VEL + Boosted ARV Regimens on TFV PK

• TFV increased when administered as TDF – story looks similar to LDV

• Limitation: raw concentrations not reported, only GMRs, so can’t evaluate against the range of TFV exposures with available safety data

Mogalian E, et al. CROI, 2/22-2/25, 2016, Boston, MA #100

Daclatasvir

• Primarily hepatically metabolized (88%), minimal renal elimination (7%)

• Dose depends on concomitant medications

Enzymes Transporters

Victim Substrate CYP3A4 Substrate P-gp

Perpetrator Inhibitor of P-gp, BCRP, OATP1B1/3

Use Full Dose DCV with DRV/r and LPV/r

• 9/12 patients that relapsed in ALLY-2 were taking DRV/r with a reduced dose of DCV (30mg)1

• Healthy volunteer PK study indicated DCV Cmax and AUC were 62% and 30% ↓, respectively when used at a reduced dose with DRV/r2

1Garimella T, et al. AASLD, 11/13-11/17, Boston, MA, #728, 2Gandhi, et al. International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, 5/26-5/28, 2015, poster #80

Grazoprevir/Elbasvir

• Hepatically metabolized, less than 1% renally eliminated

Enzymes Transporters

Grazoprevir (Protease Inhibitor)

Victim

Substrate CYP3A4 Substrate OATP1B1 and P-gp

Perpetrator

Inhibitor of CYP3A4, UGT1A1 Inhibitor of BCRP

Elbasvir (NS5A Inhibitor)

Victim Substrate CYP3A4 Substrate P-gp

Perpetrator Inhibitor of BCRP and P-gp

GZR/EBR Interaction Potential with ARV PK Changes and Recommendation

Ritonavir-boosted atazanavir GZR ↑, EBR ↑, ATV ↑

Ritonavir- boosted darunavir GZR ↑, EBR ↑, DRV ↔

Ritonavir-boosted lopinavir GZR ↑, EBR ↑, LPV ↔

Ritonavir-boosted tipranavir No data

Efavirenz GZR ↓, EBR ↓, EFV ↓

Rilpivirine GZR ↔, EBR ↔, RPV ↔

Etravirine No data

Raltegravir GZR ↔, EBR ↔, RAL ↑

Cobicistat-boosted elvitegravir No data

Dolutegravir GZR ↔, EBR ↔, DTG ↑

Maraviroc No data

Tenofovir disoproxil fumarate GZR ↔, EBR ↔, TFV ↑

Kiser JJ, www.HCVguidelines.org

PrOD

Enzymes Transporters

Ritonavir-boosted Paritaprevir (Protease Inhibitor)

Victim Substrate CYP3A4 Substrate P-gp, OATP1B1, BCRP

Perpetrator Inhibits CYP2C8, UGT1A1 (ritonavir inhibits CYP3A)

Inhibits P-gp, OATP1B1/3, BCRP

Ombitasvir (NS5A Inhibitor)

Victim Substrate CYP3A4 Substrate P-gp

Perpetrator Inhibits CYP2C8, UGT1A1

Dasabuvir (Non-nucleoside NS5B inhibitor)

Victim Substrate CYP2C8>3A4>2D6 Substrate P-gp

Perpetrator Inhibits UGT1A1 Inhibits BCRP

• Primarily hepatically metabolized, minimal renal elimination

• PrO plus ribavirin is approved for genotype 4. Many interactions are similar to PrOD, but not all.

PrOD with RPV and RAL

Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC

Comments

Not recommended theoretical concern for QTC prolongation

ok

ok

PrOD and HIV PI Interactions

Khatri A, et al. ICAAC Sept 5-9, 2014, Washington DC, *DRV package insert

Drop the ritonavir booster while on PrOD Median DRV trough is 3300 ng/mL without PrOD*, troughs are 1056-1600 with PrOD

Not recommended too much RTV

Comments

DRV PK with PrOD in HIV/HCV coinfected patients

• DRV reductions less than in healthy volunteers • 100% achieved SVR • 2 patients had HIV between 40-200 copies/mL on study, but did not appear to be

related to DRV exposures • Reassuring, but use with caution until results are available from the parent study, n=230

Wyles D, et al. CROI, 2/22-2/25, 2016, Boston, MA #574

Therapeutic Classes to Consider Class SOF/DCV GZR/EBR SOF/LDV PrOD Methadone √ √ √ √ Analgesics √ √ √ ? Anxiolytics/Sedative hypnotics/Benzos

√

√a

√

∆/X

SSRIs √ √ √ ? Oral contraceptives √ √ √ Xb

Immunosuppressants √

NOT CSA, TAC OK

√

∆

Antiepileptics (old) X X X X Statins ∆ ∆/X ?c ∆/X Calcium channel blockers √ ∆/X ? ∆

amidazolam given orally AUC increased 34%, bprogestin-containing only, LFT elevations with ethinyl estradiol, crosuvastatin not recommended, others not studied

Selected based on interaction potential and Lauffenburger JC, et al. Eur J Gastro & Hepatol 2014;26(10):1073-82

Resources for Drug Interactions

• University of Liverpool • www.hep-druginteractions.org

• Toronto General Hospital • http://www.hcvdruginfo.ca/

• Specific to antiretroviral interactions • DHHS Guidelines Drug Interaction Tables

• www.aidsinfo.nih.gov

Summary

• The primary consideration in the treatment of HIV-coinfected individuals with DAA is the potential for drug interactions

• The pharmacology of most DAA is well-defined and interactions are manageable, but there are some unknowns

• A systematic approach to the identification and management of drug interactions is imperative